¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

²Department of Ophthalmology and Visual Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest disclosure: Dr. Humphrey and Dr. Carruthers are investigators, speakers and consultants for Kythera Biopharmaceuticals and Allergan Inc.
ABSTRACT

The chin and jaw line are integral parts of an individual’s aesthetic profile, and the presence of submental fat detracts from this and can lead to displeasure with one’s facial appearance. While liposuction and cosmetic surgery are regarded as the gold standard in treating submental fat, surgical intervention is not appealing to all patients and has potential surgical complications including longer recovery, and contour irregularities. Despite ample advances in aesthetic medicine to enhance the appearance of the face, very little is available in non-invasive options to reduce submental fat that has been supported by robust evidence. ATX-101, a proprietary formulation of deoxycholic acid that is synthetically derived, has been extensively explored in a vigorous clinical development program that has established the safety and efficacy of the injectable. It has recently received approval by regulatory authorities in Canada (Belkyra™) and the US (Kybella®) for the treatment of submental fat.

Key Words: adipocytolysis, ATX-101, deoxycholic acid, injectable, nonsurgical, submental fat

Introduction

Desirable features of the face are thought to follow the “golden
ratio” or Phi that is seen in natural formations.^1,2 What is viewed as
an attractive face in contemporary culture does not significantly
differ from ancient times.³ Think of the bust of Egyptian queen
Nefertiti. The ideal face appears as an inverted triangle that
contains a wide mid-face that tapers toward the chin.^4,5 A defined
chin denotes assertiveness, credibility, and leadership.⁶ A face that
has aesthetic balance is thought to feature a neck contour that
is pleasing to the eye.⁷ Individuals who have submental fullness
may be perceived as having an unattractive profile of the chin and
may experience reduced satisfaction with their appearance which
erodes their sense of well-being.^8,9 The presence of submental fat
superficially and deep to the platysma muscle is regarded as a sign
of aging of the lower face,^10,11 but there are individuals, both young
and old, whose morphology involves a round face which includes
deposits of submental fat. Still for others, a genetic predisposition
produces undesired submental fat that detracts from their profile
and remains even with weight loss and exercise.^1,7

Surgery has been the mainstay to treat submental fullness,
colloquially referred to as the “double chin”.⁸ Complications from
surgery however make it somewhat unappealing to patients.¹²
Indeed, alternatives to surgery would be well-received by both
clinicians and patients.

Discussion

It was first observed in cell cultures and porcine skin that
sodium deoxycholate, a bile salt that occurs in the body, acts as
the active ingredient in an injectable phosphatidylcholine and
sodium deoxycholate solution that treats the accumulation of
localized fat through adipocytolysis.¹³ Other investigators later
concluded that deoxycholic acid selectively targets fat tissue
while sparing other tissues like skin and muscle in the local
environment.¹⁴ The encouraging basic research has prompted
Kythera Biopharmaceuticals, Inc. to develop a synthetic form
of deoxycholic acid, with an aim to introduce a non-injectable
therapy designed to contour the chin-neck area through
decreasing submental fat.

The synthetic compound, known as ATX-101, is manufactured using a proprietary process, is indistinguishable from endogenous deoxycholic acid given it possesses an identical chemical structure, and does not contain any substances derived
from humans or animals. Chemical compounding that produces phosphatidylcholine/sodium deoxycholate formulations is not a process that guarantees a consistent formulation¹⁵ while the proprietary manufacturing process to prepare synthetic deoxycholic acid does achieve this.

In-depth study and evaluation of deoxycholic acid for the purposes of decreasing submental fat began in 2007 with preclinical investigations to first assess the safety and side effect profile of the compound, followed by research to elucidate the pharmacokinetic, pharmacodynamic, and optimal dosing of deoxycholic acid in a clinical setting. Safety data has assured that the subcutaneous injection of 100 mg deoxycholic acid, given via 0.2-ml injections spaced at 1-cm intervals, sees a temporary rise in deoxycholic acid plasma levels, but no increase beyond the normal range of variability for endogenous deoxycholic acid, with a return to baseline levels by 24 hours post dose.^16,17 Chief among the safety observations is that injection of synthetic deoxycholic acid does not result in elevations in lipids and adipokine concentrations that are clinically significant.¹⁷

The clinical development program associated with ATX-101 has
enrolled more than 2,600 patients, of whom 1,600 patients have
been treated with the synthetic compound. Investigators have
witnessed fast absorption of the compound, as well as a decline
in overall fat in the treated area. Where needed in clinical studies,
anesthesia with topical lidocaine preparations together with ice
were provided to patients and local lidocaine injections were
performed in some cases.¹⁷

Histological data reinforce the proposed mechanism of action,
adipocytolysis (Figure 1), for deoxycholic acid.¹⁸ Injections of the
synthetic compound into abdominal fat were observed to result
in fat lobule atrophy amongst other outcomes as well as near
resolution of inflammation at 28 days, which determined the
spacing of treatments of just under one month.¹⁸ The treatment
schedule was assessed in phase III clinical trials. No histological
effects were seen in the dermis or epidermis.¹⁸

Figure 1.
Mechanism of action of deoxycholic acid. Subcutaneous administration causes the destruction of fat cells.

Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

Of note, submental fat was not decreased any further when the
area-adjusted dose of deoxycholic acid was increased through
administration of a stronger concentration, larger injection volume, or shorter intervals between injections.^19,20 Self-reported
scales, which denoted patient dissatisfaction with appearance, and
clinician-reported scales, which reflect investigator evaluations of
submental fat were employed to determine baseline appearance
as it relates to the chin in randomized, double-blind, placebocontrolled,
phase III clinical trials.^21-25 In the two North American
trials, magnetic resonance imaging (MRI) was also employed to
assess a decrease in submental volume subsequent to deoxycholic
acid injection where MRI images were interpreted in a blinded
fashion.^23,24 Post-treatment evaluations were conducted using
patient-reported instruments to determine approval with facial
appearance and appearance of the chin. Submental fat change
and its psychological effect were also evaluated, and the adverse
psychological impact of submental fat was diminished with
deoxycholic acid injection. Assessments performed at 12 weeks
after the last treatment showed that the synthetic compound
decreased submental fat based on patient, clinician, and objective
evaluations. In the North American phase III trials 68.2% of
ATX-101 (2 mg/cm²) subjects demonstrated a simultaneous
improvement of at least one grade from baseline on clinician and
patient reported rating scales vs. 20.5% in placebo (p<0.001). The
proportion of MRI responders was more than eight-fold greater
with the compound than placebo in the REFINE-1 trial.^21-24

While there are predefined maximum treatments based on phase
III clinical data – four treatments based on European data and
six treatments based on North American data – fewer treatments
may be administered if efficacy is achieved earlier or if there
are safety concerns. After two treatments, 52.2% of subjects
achieved at least a one grade change from baseline in the clinician
submental fat ratings, and 71.5% after four treatments^21-24, endorsing the concept of tailored treatment of deoxycholic acid
for each patient, taking into account factors such as individual
anatomy and the fact the quantity of submental fat decreases over
time with successive treatments. See Figures 2a and 2b for before
and after images.^23,24 Durability is another favorable property
of deoxycholic acid therapy.²⁴ Data bear out that the effect of
treatment is sustained for up to 4 years after the last injection.²⁴

Figure 2a.
REFINE-2 (ATX-101-11-23) study – unretouched photos of clinical trial patient taken before and after treatment with ATX-101.

Subject details: Age: 35, Sex: F, Number of treatment cycles: 4, Composite grade change: 1-grade, Total dose: 16.2 ml

CR-SMFRS = Clinician-Reported Submental Fat Rating Scale; PR-SMFRS = Patient-Reported Submental Fat Rating Scale

Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

Figure 2b.
REFINE-1 (ATX-101-11-22) study – unretouched photos of clinical trial patient taken before and after treatment with ATX-101.

Subject details: Age: 55, Sex: F, Number of treatment cycles: 5, Composite grade change: 1-grade, Total dose: 22.0 ml

Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

The majority of adverse events in the four phase III trials
associated with deoxycholic acid injections were mild or
moderate, and transient. Pain, swelling, bruising, numbness,
erythema, and induration were some of the most frequent
side effects and were linked to the treatment area, route of
administration, the mechanism of action of the compound, and
expected tissue response. With repeated treatments, the incidence
and severity of pain and swelling declined.²³ Serious adverse
events were infrequent.²³ One adverse event, albeit rare, that did
differ between placebo-treated patients and deoxycholic acidtreated
patients was marginal mandibular nerve (MMN) paresis,
but most instances of MMN paresis were mild or moderate in
severity, lasting a median duration of 47.5 days.²³ No new signals
related to safety have been detected in extended follow up.

Phase III clinical trials demonstrated no exacerbation of skin
laxity, which is traditionally a worry when fat is extracted from
a targeted zone. In actual fact, skin laxity remained the same or
was improved in phase III clinical trials.^21,24 It has been suggested
the absence of exacerbation of skin laxity could be attributed to
the phenomenon of neocollagenesis,¹⁸ which was observed in
histologic samples after treatment with deoxycholic acid. Happily
for patients, the data indicate procedures for skin tightening to
address skin laxity are not necessary after submental fat decrease
with deoxycholic acid therapy.

Conclusion

As a first-in-class injectable therapy, deoxycholic acid, was
recently approved by Health Canada and the US Food and Drug
Administration, as Belkyra™ and Kybella®, respectively, to treat
submental fullness. It is not approved for use in other facial
areas or sites on the body. As a minimally invasive treatment,
it can be performed in the office, results are visible in two to
four treatments, and recovery is relatively quick. Different from
facial injectables like fillers and neuromodulators, maintenance
treatments with deoxycholic acid are not required to sustain
the effect over time or to reduce skin laxity. Clinicians should
ensure sufficient submental fat is present to justify injection of
deoxycholic acid. They should also be cautious to avoid injuring
anatomic structures in the submental region when injecting the
synthetic compound.

Acknowledgement

The authors wish to acknowledge Louise Gagnon for her editorial
assistance in the preparation of this manuscript.

References

1. Huettner F, Vasconez LO, de la Torre JI. Neck rejuvenation–anatomy and clinical correlation. Facial Plast Surg. 2012 Feb;28(1):40-51.
2. Ellenbogen R, Karlin JV. Visual criteria for success in restoring the youthful neck. Plast Reconstr Surg. 1980 Dec;66(6):826-37.
3. Sands NB, Adamson PA. Global facial beauty: approaching a unified aesthetic ideal. Facial Plast Surg. 2014 Apr;30(2):93-100.
4. Dayan SH, Arkins JP, Patel AB, et al. A double-blind, randomized, placebo-controlled health-outcomes survey of the effect of botulinum toxin type a injections on quality of life and self-esteem. Dermatol Surg. 2010 Dec;36 Suppl 4:2088-97.
5. Swift A, Remington K. BeautiPHIcation: a global approach to facial beauty. Clin Plast Surg. 2011 Jul;38(3):347-77, v.
6. Chin surgery skyrockets among women and men in all age groups. American Society of Plastic Surgeons. Press release dated April 16, 2012.
7. Raveendran SS, Anthony DJ, Ion L. An anatomic basis for volumetric evaluation of the neck. Aesthet Surg J. 2012 Aug;32(6):685-91.
8. Rohrich RJ, Rios JL, Smith PD, et al. Neck rejuvenation revisited. Plast Reconstr Surg. 2006 Oct;118(5):1251-63.
9. Schlessinger J, Weiss SR, Jewell M, et al. Perceptions and practices in submental fat treatment: a survey of physicians and patients. Skinmed. 2013 Jan-Feb;11(1):27-31.
10. Ascher B. Developments in management of facial and body lipoatrophy with exogenous volumetric injectables. In: Landau M, Rossi B, editors. Injection treatments in cosmetic surgery. London, UK: Informa Healthcare. 2008: p329-38.
11. Burgess CM. Principles of soft tissue augmentation for the aging face. Clin Interv Aging. 2006 1(4):349-55.
12. Koehler J. Complications of neck liposuction and submentoplasty. Oral Maxillofac Surg Clin North Am. 2009 Feb;21(1):43-52, vi.
13. Rotunda AM, Suzuki H, Moy RL, et al. Detergent effects of sodium deoxycholate are a major feature of an injectable phosphatidylcholine formulation used for localized fat dissolution. Dermatol Surg. 2004 Jul;30(7):1001-8.
14. Thuangtong R, Bentow JJ, Knopp K, et al. Tissue-selective effects of injected deoxycholate. Dermatol Surg. 2010 Jun;36(6):899-908.
15. Gupta A, Lobocki C, Singh S, et al. Actions and comparative efficacy of phosphatidylcholine formulation and isolated sodium deoxycholate for different cell types. Aesthetic Plast Surg. 2009 May;33(3):346-52.
16. Walker P, Fellmann J, Lizzul PF. A phase I safety and pharmacokinetic study of ATX-101: injectable, synthetic deoxycholic acid for submental contouring. J Drugs Dermatol. 2015 Mar;14(3):279-87.
17. Walker P, Lee D. A phase 1 pharmacokinetic study of ATX-101: serum lipids and adipokines following synthetic deoxycholic acid injections. J Cosmet Dermatol. 2015 Mar;14(1):33-9.
18. Walker P, Lee D, Toth BA. A histological analysis of the effects of single doses of ATX-101 on subcutaneous fat: results from a phase I open-label safety study of ATX-101. Poster presentation. 2013 Annual Meeting of the American Society for Dermatologic Surgery. October 3-6, 2013. Chicago, IL.
19. KYTHERA Biopharmaceuticals, Inc. FDA briefing document, April 30, 2015.
20. Goodman G, Smith K, Walker P, et al. Reduction of submental fat with ATX-101: a pooled analysis of two international multicenter, double-blind, randomized, placebocontrolled studies. J Am Acad Dermatol. 2012 Apr;66(4 Suppl 1):AB11.
21. Ascher B, Hoffmann K, Walker P, et al. Efficacy, patient-reported outcomes and safety profile of ATX-101 (deoxycholic acid), an injectable drug for the reduction of unwanted submental fat: results from a phase III, randomized, placebo-controlled study. J Eur Acad Dermatol Venereol. 2014 Dec;28(12):1707-15.
22. Rzany B, Griffiths T, Walker P, et al. Reduction of unwanted submental fat with ATX-101 (deoxycholic acid), an adipocytolytic injectable treatment: results from a phase III, randomized, placebo-controlled study. Br J Dermatol. 2014 Feb;170(2): 445-53.
23. Humphrey S, Sykes J, Kantor J, et. al. REFINE-2: A randomized, double-blind, placebocontrolled, phase III trial evaluating the efficacy and safety of deoxycholic acid injection (ATX-101) for submental contouring. J Am Acad Dermatol. (Submitted)
24. Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat reduction. Dermatol Surg. 2016 Jan;42(1):38-49.
25. Hoffmann K, et al. Reductions in submental fat achieved with ATX-101 (deoxycholic acid) are maintained over time. 13th Aesthetic & Anti-Aging Medicine World Congress. March 26-28, 2015. Monte Carlo, Monaco.

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Introduction

Acne vulgaris (AV) is among the most common dermatological disorders seen by dermatologists, affecting approximately 85% of people between the ages of 12 and 24 years.¹ Emerging evidence suggests that acne is associated with epidermal barrier impairments, including stratum corneum (SC) barrier permeability.² There is also mounting evidence to demonstrate an association between AV and inherent epidermal barrier dysfunction involving increased filaggrin expression and decreased ceramide levels.² While topical therapy remains a key therapeutic approach in the clinical management of AV, it can be associated with side effects that may compromise the SC and impair patient adherence. The use of adjunctive cleansers and moisturizers can help mitigate treatment side effects and subsequently enhance therapeutic efficacy.

Pathophysiology & Clinical Presentation

• The four main pathophysiologic features of AV are:³
  1. Androgen-mediated stimulation of sebaceous gland activity
  2. Abnormal keratinization leading to follicular plugging (comedone formation)
  3. Proliferation of Propionibacterium acnes (P. acnes) within the follicle
  4. Inflammation
• Genetic factors, stress and diet may also influence the development of acne.
• Some data suggest that patients with AV suffer from inherently compromised facial SC barrier permeability, and that the severity of AV may correlate with the degree of SC barrier impairment and decreased levels of free sphingosine and total ceramides, suggesting a deficiency of the intercellular lipid membrane.²
• Some medications used to treat AV can alter SC integrity and function, either via the active ingredient, the vehicle, or both. This can result in signs and symptoms of cutaneous irritation such as erythema, scaling and a burning or stinging sensation.²
• Recent data show that the experience of just one treatment-related side effect (e.g., irritation, dryness, redness) significantly, negatively impacts adherence to acne treatment.⁴

Topical Therapy

Topical therapy is used for mild to moderate acne and also for maintenance therapy in all severity levels (Table 1).

• Evidence-based treatment guidelines recommend fixed-dose combination topical benzoyl peroxide (BPO)-adapalene or BPOclindamycin for treatment of mild-moderate papulopustular acne.⁵
• Retinoids are comedolytic, anticomedogenic and anti-inflammatory.
• BPO is an antimicrobial agent that has some keratolytic effects and does not contribute to antibiotic resistance.
• Antibiotics have antimicrobial and anti-inflammatory effects. They can be used in conjunction with BPO lotion, gel or wash to limit antibiotic resistance. They should not be used for maintenance therapy.
• Topical dapsone gel is antimicrobial and antineutrophilic.
• New fixed-dose retinoid-based combination therapies are available (e.g., tretinoin and clindamycin)
• Both topical retinoids and BPO can cause symptoms of skin irritation.

Cleansers & Moisturizers

• The goal of cleansing for patients with acne or acne-prone skin is to remove surface dirt, sweat, excess oil, exfoliated cells and micro-organisms without irritating or disrupting the skin’s protective barrier.
• Regular use of mild cleansers is an important component of effective acne management as a hydrated SC absorbs medication more readily and is less prone to irritation.
• Routine cleansing may enhance antimicrobial activity and decrease the risk of infection.
• Simplified treatment and skin care regimes should be recommended, including the use of an appropriate moisturizer and washing with a mild, soap-free cleanser twice daily.⁴

Types of Cleansers

• To date, limited published data exist to inform the clinical management of AV with regard to cleansers and moisturizers. Recommendations are based largely on general knowledge (e.g., non-soap based cleansers).
• Ideally, cleansers for acne skin should be: non-comedogenic, non-acnegenic, non-irritating, and non-allergenic.⁶
• A wide spectrum of skin cleansing agents exist for acne ranging from lipid free cleansers, syndets and astringents to exfoliants and abrasives.⁷
• Anionic detergents (i.e., soaps) can alter the natural pH of skin, which is normally between 5.3 and 5.9.
• An increase in pH can result in increased transepidermal water loss (TEWL), which causes dryness. Further, an increase in pH may facilitate microbial growth, which can exacerbate AV.⁸
• Abrasive cleansers can promote SC barrier dysfunction and contribute to signs and symptoms of irritation: these should be avoided.
• Suitable cleansers for acne-prone skin are generally based on mild synthetic surfactants that minimize the potential for skin barrier disturbances.
  • Non-ionic surface-acting agents (e.g., silicone and polysorbate) are less likely to cause irritation and are formulated to the same pH as the skin (5.5).
  • Silicone surfactants (e.g., dimethicone) such as Spectro®, are effective at eliminating surface debris without completely stripping away protective oils.
  • Cleansers that contain zinc coceth and zinc gluconate, such as Cetaphil® DermaControl, also provide astringent properties without irritation or alteration to the pH level of the skin, and the zinc complex absorbs excess oil for a matte appearance of the skin.
  • Cleansers containing emollients, such as Cetaphil® DermaControl, Effaclar, Spectro® and Cetaphil® Gentle Skin Cleanser can minimize damage to the SC barrier by emulsifying dirt and oil for easy removal. Additionally, Cetaphil® DermaControl contains humectants, which attract moisture to the skin in order to alleviate the drying effects of cleansing.

Types of Moisturizers

• Effective moisturizers combine humectants and emollients to prevent or reduce water evaporation, draw moisture up from deeper layers, alleviate xerosis and maintain skin barrier integrity.
• Moisturizers should also prevent primary irritation.
• Broad spectrum UVA/UVB sun protection is also important for patients with AV, particularly for those on topical and systemic retinoid therapy.⁹
• The different types of moisturizers include (Table 2):
  1. Occlusives
  2. Humectants
  3. Emollients
  4. Protein rejuvenators¹⁰
  5. Ceramide dominant
• Moisturizers containing ceramides have recently entered the market and work to replace naturally occurring lipids in the SC.
• The only published clinical trial data studying an adjunctive moisturizer in AV patients concerns Cetaphil® DermaControl. It contains ceramides and an oil-absorbing zinc complex. It is non-comedogenic, non-irritating, nonacnegenic and non-greasy.
• The recent development of oleosome technology, which is also present in Cetaphil® DermaControl, enables the delivery of broad spectrum UVA/UVB sun protection (SPF 30). This technology effectively reduces the concentration of filters being applied to the skin, decreasing the potential for skin sensitivity reactions.⁹

Acne Therapy & Adherence

• Treatment adherence in patients with AV is a significant problem and is documented at approximately 50%.⁴
• An estimated 30-40% of patients using topical acne treatment formulations do not comply with their prescribed regimen.¹¹
• Clinical variables that have been shown to negatively impact adherence include age, patient satisfaction with treatment, and knowledge about acne treatment.⁴
• Irritation resulting from topical medications and the emergence of bacterial resistance to both topical and oral antibiotics remain significant barriers to good treatment adherence.
• Recent advances in vehicle technology have improved efficacy, local tolerance and adherence.¹²
• Additionally, novel delivery mechanisms and vehicles, such as pumps and foams, are convenient and preferred by patients, which may also improve adherence.¹³
• The appropriate selection and use of moisturizers has positive effects on treatment adherence.⁴
• Patient satisfaction with treatment and clinical improvement as evaluated by a dermatologist have been shown to improve treatment adherence and may also improve patient self-esteem.4
• Discuss realistic treatment expectations with patients and consider dosing strategies that can enhance adherence (Table 3).

Adjunctive Skin Care in Acne: Clinical Evidence

• Alleviating dryness and improving skin comfort by using a moisturizer concomitantly with retinoid therapy could enhance treatment efficacy. Data from a randomized, splitface study showed the application of a moisturizing cream applied twice daily for 15 days by patients taking either oral isotretinoin (10-20 mg) for two months or topical tretinoin 0.05% for one month provided significant improvements, compared with baseline, in the levels of skin dryness, roughness and desquamation induced by either drug.¹⁴ As well, skin properties and discomfort were substantially improved.
• Results from a study evaluating a facial moisturizer with SPF 30 and ceramide precursor formulated for blemish prone skin with 0.05% tretinoin found a patient preference for the moisturizer.⁹ It was a randomized, investigator-blinded, split-face study assessing erythema, scaling and dryness in patients with blemish prone skin. While both sides developed skin irritation, it worsened in the non-moisturized sides. Notably, all five parameters, namely erythema, scaling, dryness, stinging/burning and pruritus were improved on the sides treated with moisturizer.
• Adjunctive use of moisturizer with a topical tretinoin cream improved tolerance of the treatment.⁹

Conclusion

Skin barrier impairment in patients with AV can negatively impact acne treatment. Therefore, providing patient-specific skin care recommendations, including product selection and proper use, is an important part of the clinical management of AV and may improve patient tolerance to treatment.² The adjunctive use of appropriate gentle soap-free cleansers and non-comedogenic moisturizers, ideally products that also restore SC barrier function, provide SPF protection and reduce side effects of topical acne therapy, are recommended. Moreover, they are preferred by patients and will likely improve treatment adherence.

References

1. Leyden JJ. J Am Acad Dermatol. 2003 Sep;49(3 Suppl):S200-10.
2. Thiboutot D, et al. J Clin Aesthet Dermatol. 2013 Feb;6(2):18-24.
3. Haider A, et al. JAMA. 2004 Aug;292(6):726-35.
4. Dreno B, et al. Int J Dermatol. 2010 Apr;49(4):448-56.
5. European Dermatology Forum Guideline on Treatment of Acne.
6. Solomon BA, et al. Clin Dermatol.1996 Jan-Feb;14:95-9.
7. Mukhopadhyay P. Indian J. Dermatol.2011 Jan-Feb;56(1): 2-6.
8. Decker A, et al. J Clin Aesthet Dermatol. 2012 May;5(5): 32-40.
9. Schorr E, et al. J.Drugs in Dermatol. 2012 Sep;11(9) 957-60.
10. Lynde CW. Skin Therapy Lett. 2001. Dec;6(13):3-5.
11. Finlay AY. J Eur Acad Dermatol Venereol. 1999 Sep;12(Suppl 2):S77.
12. Koo J. Skinmed. 2003 Jul-Aug;2(4):229-33.
13. Vender R, et al. Patient preferences in acne: a point-of-care educational initiative. Poster presentation.
14. Laquieze S, et al. J Drugs Dermatol. 2006 Nov-Dec;5(10):985-90.

Key Words:
acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, topical combination therapy

Antibiotic Resistance in Acne Therapy

Propionibacterium acnes (P. acnes) is an anaerobic bacteria implicated in the pathogenesis of acne vulgaris. There are four primary pathogenic factors: excess sebum production, bacterial colonization, inflammation, and abnormal keratinization.¹ Treatment targets as many pathogenic factors as possible and may include a combination of topical and systemic agents.

Although current acne guidelines discourage the use of antibiotics as prolonged monotherapy,¹ about 5 million prescriptions for oral antibiotics are written each year for the treatment of acne.² Antibiotics demonstrate anti-inflammatory and antimicrobial effects and work on two levels: to decrease the presence of P. acnes – a resident of the normal microflora found in abnormally high numbers in the sebaceous follicles of patients with acne and a primary factor in the development of inflammatory acne³ – and to inhibit the production of P. acnes-associated inflammatory mediators.⁴ Indeed, topical and oral antibiotics have been the mainstay of acne treatment for over 50 years.

In 1976, there was no evidence of antibiotic-resistant propionibacteria on the skin of over 1000 patients with acne.⁵ By 1979, Crawford and colleagues had detected the first indication of resistance to topical erythromycin and clindamycin,⁶ which was followed by the emergence of tetracycline-resistant P. acnes in the early eighties.⁷ Since then, the incidence of antibiotic resistance in acne has continued to rise across the globe, from 20% in 1978 to 72.5% in 1995,⁸ with combined resistance to erythromycin and clindamycin more prevalent than resistance to tetracycline.⁹ Evidence suggests that it is the use of topical erythromycin and clindamycin – the most commonly used topical antibiotics in acne – that has contributed to the gradual increase in resistance over the last 20 years.^7,8,10-12 In fact, resistant P. acnes strains have been shown to emerge after only 8 weeks of topical antibiotic monotherapy, with the number of resistant strains increasing progressively over subsequent weeks.¹³

Evidence of Clinical Relevance

Acne does not represent a typical bacterial infection, in which antibiotic resistance directly correlates to treatment failure, because antibiotics demonstrate both antibacterial and anti-inflammatory effects, and P. acnes – existing in the microaerophilic or anaerobic and lipid-rich environment of the pilosebaceous follicle – cannot easily be cultured. However, it is logical to assume that resistance manifests with a reduced clinical response, and this theory is substantiated by the results of several investigations linking resistant strains to higher counts of P. acnes and therapeutic failure.^7,10,14,15 A systematic review of 50 clinical trials using topical antibiotics between 1974 and 2003 paints a startling picture: a significant decrease in the efficacy of topical erythromycin on inflammatory and non-inflammatory lesions over time (Figure 1).¹⁶

The question remains: what does it matter? While it is true that that the prevalence of life-threatening infections caused by P. acnes has greatly increased in the last twenty-odd years,¹⁷ most often in the post-surgical setting in patients with significant medical comorbidities,¹⁸ acute propionibacterial infections are never treated with acne medication. Furthermore, it would seem that antibiotic-resistant acne puts neither patients nor the community at risk for resistant propionibacterial infections.

Figure 1: Impact on acne: efficacy of topical erythromycin over time (empty circles: studies evaluating treatment efficacy after 8 weeks; asterisks: studies evaluating treatment efficacy after 12 weeks). Figure from Simonart T, Dramaix M., Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol. 2005 Aug;153(2):page 399, Figure 1. Reprinted with permission from John Wiley and Sons.

Resistance in Pathogenic Organisms

Prolonged regimens using either topical or oral antibiotics for the treatment of acne have resulted in selection pressure or the transfer of resistant genes to potentially pathogenic bacteria, such as certain strains of staphylococci or streptococci,^4,6 and it is these resistant organisms that could present clinical challenges. Levy and colleagues investigated the effects of topical and/or oral antibiotics on the oropharyngeal flora in patients with acne.¹⁹ Patients treated with any antibiotic exhibited a 3-fold greater risk of group A streptococcus colonization by Streptococcus pyogenes (S. pyogenes) compared to patients not using antibiotic therapy. Eighty-five percent of S. pyogenes cultures from those using antibiotics were resistant to at least one tetracycline antibiotic, compared to 20% from those not using antibiotics.

A subgroup analysis of topical versus oral antibiotics found similar prevalence rates, indicating that topical antibiotics have an impact on distant flora and resistance patterns by direct inoculation or systemic absorption. Like their oral counterparts, topical antibiotics may alter the microbial equilibrium through selective elimination of certain bacteria, allowing species like S. pyogenes, which would normally be held in check, to flourish.¹⁹

Studies have clearly demonstrated that the use of topical erythromycin increases counts of resistant coagulase-negative staphylococci (CNS) on both local and distant anatomical sites.^20-22 Harkaway and colleagues demonstrated aerobic flora dominated by Staphylococcus epidermidis (S. epidermidis) completely resistant to erythromycin and partially resistant to clindamycin and tetracycline after 12 weeks of treatment.²⁰ Vowels and colleagues found that the prevalence and density of resistant organisms persisted and did not return to baseline values until 6 weeks after discontinuation of topical antibiotic therapy.²¹

The implications are potentially serious. S. epidermidis has been found to be pathogenic in certain patients, predominantly those with indwelling catheters, surgical patients, or premature infants.^23-25 More ominously, CNS has been shown to transfer resistance to the more pathogenic S. aureus,²⁶ which tends to thrive and disseminate more widely in conjunction with topical antibiotic therapy. In a 24-week randomized trial of 2% erythromycin gel versus its vehicle, antibiotic therapy led to an increase from 15% to 40% in erythromycin-resistant S. aureus carriage rates in the nose, and resistance increased significantly and substantially in the treated group versus patients receiving vehicle (63% vs. 37%) by the end of the treatment period.²²

For all the potentially pathogenic organisms that develop resistance to anti-acne antibiotics, the question remains: does it really matter? Physicians are unlikely to treat S. epidermidis or group A streptococcus with acne medication. However, consider this: first-line systemic agents for community-acquired methecillin-resistant S. aureus (MRSA) include minocycline and trimethoprim-sulfamethoxazole, both of which are used for the treatment of acne. Thus far, resistance to minocycline is not common; the same cannot be said about trimethoprim.²⁷ As multi-drug-resistant organisms emerge, therapeutic options continue to shrink.

Antibiotic Resistance in Acne Treatment: Evidence of Clinical Relevance

• Reduced clinical response to antibiotic therapy
• Potential increase in pathogenicity of P. acnes
• Transfer of resistance to more pathogenic organisms

Strategies to Limit Resistance

Since prescribing practice patterns directly influence the rates of P. acnes resistance in the population (i.e., the levels of resistance correlate to the levels of antibiotic use), and since selection pressure may affect more pathogenic bacteria than P. acnes, it makes sense to implement strategies and guidelines to limit antibiotic resistance.¹ The Global Alliance to Improve Outcomes in Acne guidelines recommend the combination of a topical retinoid plus an antimicrobial agent as first-line therapy for most patients with acne.¹ When antibiotics are indicated, the guidelines recommend strategies to limit resistance, including the use of oral antibiotics only in moderate and moderately severe cases of acne, and the necessary addition of benzoyl peroxide (BPO) and a topical retinoid to regimens using topical antibiotics in mild-tomoderate cases.

Strategies to Limit Antibiotic Resistance in Acne

• Avoid topical or oral antibiotics as monotherapy or maintenance therapy
• Limit duration of antibiotic use and assess response at 6 to 12 weeks
• Use concomitant BPO (leave-on or wash)
• Avoid simultaneous use of oral and topical antibiotics without BPO
• Use topical retinoid +/- BPO as maintenance in lieu of antibiotics

Evidence suggests that BPO, alone or in combination with a topical retinoid, may serve as an effective and well tolerated option for treating acne in patients with resistant P. acnes, while minimizing the development of further antibiotic resistance. Topical retinoids exhibit both anti-inflammatory and anticomedonal activities¹¹ and are highly effective in reducing both inflammatory and non-inflammatory lesions.^28,29 BPO is a broad-spectrum antibacterial agent that comes in many formulations and works through the interaction of oxidized intermediates with various constituents of microbial cells.³⁰ Despite its widespread use, bacterial resistance has not been reported.

Leave-on products containing BPO not only suppress existing insensitive strains, but also reduce the emergence of erythromycin- and clindamycin-resistant strains during antibiotic therapy.^13,15,30-35 Moreover, the concomitant use of BPO with a topical antibiotic is highly effective in reducing the colony counts of cutaneous P. acnes.^20,33,36 Even simple washes containing BPO effectively reduce P. acnes,^11,37 including resistant populations.³⁹ Leyden and colleagues assessed the effectiveness of a gel combination treatment containing 0.1% adapalene and 2.5% BPO in healthy patients with high P. acnes populations resistant to erythromycin, tetracycline and clindamycin, and found a significant reduction in resistant strains by week 4.¹² Indeed, therapy with a combination of adapalene and BPO eradicated some resistant strains entirely in some patients.

Subantimicrobial Dosing

There is some evidence that subantimicrobial doses of antibiotics may reduce inflammation and provide immunomodulatory effects without risk of any resistance. Doxycycline is a secondgeneration tetracycline class antibiotic normally used at a dose of 100 mg to 200 mg/day in the treatment of acne. Skidmore randomized 51 patients with moderate acne to twice daily 20 mg doses of doxycycline or placebo for 6 months.³⁹ Active treatment significantly reduced the number of inflammatory and non-inflammatory lesions by more than 50% and led to a greater overall improvement compared to placebo, with no change in number or severity of resistant pathogens or evidence of antimicrobial effect on the skin flora. Toossi and colleagues compared subantimicrobial doses (20 mg twice daily) with antimicrobial doses (100 mg daily) in a prospective, double-blind, randomized controlled trial of 100 patients with moderate facial acne.⁴⁰ Both treatments significantly decreased inflammatory lesion counts; subantimicrobial dosing led to an 84% and 90% reduction in the number of papules and pustules, respectively. Although more rigorous trials designed to study the impact on follicular and cutaneous microflora and resistance patterns are warranted, these early results are promising and may represent a future possibility for the management of acne vulgaris.

Conclusion

Although antibiotics play an important role in acne management, the increase in P. acnes resistance should be cause for concern and serve as the impetus for change in prescribing patterns and treatment algorithms. Not only are resistant strains linked to lack or worsening of clinical response to treatment, but the pathogenicity of P. acnes has increased over recent years, and most importantly prolonged regimens of antibiotic therapy have led to the transfer of resistance among non-targeted pathogenic bacteria. Limiting the frequency and duration of antibiotic use and adding the topical antimicrobial agent BPO will minimize the development of resistance while maintaining efficacy in the treatment of inflammatory and non-inflammatory acne lesions.

References

1. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009 May;60(5 Suppl):S1-50.
2. Stern RS. Medication and medical service utilization for acne 1995-1998. J Am Acad Dermatol. 2000 Dec;43(6):1042-8.
3. Webster GF. Acne vulgaris. BMJ. 2002 Aug 31;325(7362):475-9.
4. Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment of acne vulgaris and other inflammatory skin disorders: focus on antibiotic resistance. Cutis. 2007 Jun;79(6 Supp™l):9-25.
5. Leyden JJ. Antibiotic resistant acne. Cutis. 1976 Mar;17(3):593-606.
6. Crawford WW, Crawford IP, Stoughton RB, et al. Laboratory induction and clinical occurrence of combined clindamycin and erythromycin resistance in Corynebacterium acnes. J Invest Dermatol. 1979 Apr;72(4):187-90.
7. Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol. 1983 Jan;8(1):41-5.
8. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust. 1998 Sep 7;169(5):259-61.
9. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol. 2003 Mar;148(3):467-78.
10. Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol. 1989 Jul;121(1):51-7.
11. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1-37.
12. Leyden JJ, Preston N, Osborn C, et al. In-vivo effectiveness of adapalene 0.1%/benzoyl peroxide 2.5% gel on antibiotic-sensitive and resistant Propionibacterium acnes. J Clin Aesthet Dermatol. 2011 May;4(5):22-6.
13. Cunliffe WJ, Holland KT, Bojar R, et al. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002 Jul;24(7):1117-33.
14. Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology. 2003;206(1):54-6.
15. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet. 2004 Dec 18-31;364(9452):2188-95.
16. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol. 2005 Aug;153(2):395-403.
17. Jakab E, Zbinden R, Gubler J, et al. Severe infections caused by Propionibacterium acnes: an underestimated pathogen in late postoperative infections. Yale J Biol Med. 1996 Nov-Dec;69(6):477-82.
18. Oprica C, Nord CE. European surveillance study on the antibiotic susceptibility of Propionibacterium acnes. Clin Microbiol Infect. 2005 Mar;11(3):204-13.
19. Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol. 2003 Apr;139(4):467-71.
20. Harkaway KS, McGinley KJ, Foglia AN, et al. Antibiotic resistance patterns in coagulase-negative staphylococci after treatment with topical erythromycin, benzoyl peroxide, and combination therapy. Br J Dermatol. 1992 Jun;126(6):586-90.
21. Vowels BR, Feingold DS, Sloughfy C, et al. Effects of topical erythromycin on ecology of aerobic cutaneous bacterial flora. Antimicrob Agents Chemother. 1996 Nov;40(11):2598-604.
22. Mills O, Jr., Thornsberry C, Cardin CW, et al. Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta Derm Venereol. 2002;82(4):260-5.
23. Lowy FD, Hammer SM. Staphylococcus epidermidis infections. Ann Intern Med. 1983 Dec;99(6):834-9.
24. Gemmell CG. Coagulase-negative staphylococci. Med Microbiol. 1986 Dec;22(4):285-95.
25. Stillman RI, Wenzel RP, Donowitz LC. Emergence of coagulase negative staphylococci as major nosocomial bloodstream pathogens. Infect Control. 1987 Mar;8(3):108-12.
26. Naidoo J, Noble WC. Skin as a source of transferable antibiotic resistance in coagulase-negative staphylococci. Zentralblatt Bakt Suppl. 1987;16:225-34.
27. Eady EA, Jones CE, Gardner KJ, et al. Tetracycline-resistant propionibacteria from acne patients are cross-resistant to doxycycline, but sensitive to minocycline. Br J Dermatol. 1993 May;128(5):556-60.
28. Thiboutot DM, Shalita AR, Yamauchi PS, et al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigatorblind follow-up of a recent combination study. Arch Dermatol. 2006 May;142(5):597-602.
29. Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, doubleblind, randomized, parallel-group study. Arch Dermatol. 2006 May;142(5): 605-12.
30. Eady EA, Farmery MR, Ross JI, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from acne patients. Br J Dermatol. 1994 Sep;131(3):331-6.
31. Bojar RA, Cunliffe WJ, Holland KT. The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol. 1995 Feb;132(2):204-8.
32. Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin-resistant propionibacteria. Br J Dermatol. 1996 Jan;134(1): 107-13.
33. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol. 1997 Oct;37(4):590-5.
34. Leyden J, Levy S. The development of antibiotic resistance in Propionibacterium acnes. Cutis. 2001 Feb;67(2 Suppl):21-4.
35. Thiboutot D. Acne: 1991-2001. J Am Acad Dermatol. 2002 Jul;47(1):109-17.
36. Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol. 2001;15 Suppl 3:51-5.
37. Gans EH, Kligman AM. Comparative efficacy of clindamycin and benzoyl peroxide for in vivo suppression of Propionibacterium acnes. J Dermatolog Treat. 2002 Sep;13(3):107-10.
38. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008 Dec;82(6): 417-21.
39. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003 Apr;139(4):459-64.
40. Toossi P, Farshchian M, Malekzad F, et al. Subantimicrobial-dose doxycycline in the treatment of moderate facial acne. J Drugs Dermatol. 2008 Dec;7(12): 1149-52.

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Introduction

Acne vulgaris is a common disorder of the pilosebaceous follicle with multiple pathogenic factors. While previous anti-acne treatment algorithms focused on antibiotics, the incidence of antibiotic resistance and the availability of more effective, well-tolerated topical agents have led to new treatment paradigms. The 2009 Global Alliance to Improve Outcomes in Acne guidelines1 recommend that mild to moderate acne is best treated with retinoid-based topical agents. In addition, acne is increasingly recognized as a chronic disorder with a pattern of recurring outbreaks and important social and psychological effects. Aggressive treatment of acne at clinical onset, followed by maintenance therapy, is recommended in order to reduce the duration of active acne and in turn decrease the likelihood of physical scarring and psychological impact.

Overview

Pathogenesis

• Four main pathogenic factors interact to cause acne:¹
  1. Abnormal follicular keratinization and desquamation
  2. Excess production of sebum
  3. Bacterial colonization of pilosebaceous duct by Propionibacterium acnes (P. acnes)
  4. Inflammation
• Hygiene, beyond gentle twice-daily cleansing, has a negligible effect on acne development or resolution.
• The evidence implicating diet in the pathogenesis of acne is inconclusive, but high glycemic diets and dairy may contribute.²
• Acne formation begins with the microcomedone, a clinically invisible lesion. Microcomedones then develop into visible acne lesions: comedones, papules, pustules, and nodules. The degree of inflammation is variable.

Prevalence and Diagnostic Features

• The pilosebaceous unit is found in highest concentrations on the face, chest, and back, explaining the clinical distribution of acne.
• About 80% of people between the ages of 11-30 years are affected2 and up to 50% of affected individuals continue to have acne as adults.¹
• Acne is characterized by polymorphous lesions:
  • Non-inflammatory – open and closed comedones
  • Inflammatory – papules, pustules, and nodules
• Acne can also be classified by severity:
  • Mild – comedonal and papular/pustular
  • Moderate – papular/pustular and nodular
  • Severe – scarring, acne conglobata or fulminans
• Acne is best approached as a chronic disease^1,3 because of its relapsing and recurring pattern, prolonged course, manifestation as acute outbreaks or slow onset, and psychological and social impacts. The psychological sequelae of acne may not correlate with disease severity.

Treatment Rationale

• Sixty percent of acne cases can be managed with acute therapy followed by topical maintenance treatment.¹
• The goal of therapy is to treat visible acne, then continue maintenance to prevent the formation of microcomedones.
• Treatment can prevent or reduce negative outcomes, such as scarring, hyperpigmentation, depression, anxiety, and social withdrawal.
• Treatment should target multiple pathogenic factors.
• The historical approach of using topical or systemic antibiotic monotherapy to target P. acnes contributes to antibiotic resistance.
• Topical therapy of a retinoid plus an antimicrobial (benzoyl peroxide, or benzoyl peroxide + antibiotic) targets 3 of the 4 pathogenic factors while avoiding systemic effects and antibiotic resistance.

Topical Treatment Options

• Level 1 evidence shows combination retinoid-based therapy is first-line for acne treatment and it targets 3 of the 4 pathogenic factors: P. acnes colonization, inflammation, and abnormal desquamation.¹
• Retinoids are comedolytic, anticomedogenic, and antiinflammatory.
• Benzoyl peroxide (BPO) is an antimicrobial agent that has some keratolytic effects and does not contribute to antibiotic resistance.
• Antibiotics have antimicrobial and anti-inflammatory effects, but they should be used in conjunction with BPO lotion, gel or wash to limit antibiotic resistance, and should not be used for maintenance therapy.
• New fixed-dose retinoid-based combination therapies are available.
  • Patient adherence is improved with once daily dosing of a single formula.
  • Retinoid-BPO formulations may be preferable over retinoid-antibiotic formulations because there is no risk of developing bacterial resistance.¹

New Fixed-dose Combination Acne Treatments

Adapalene-Benzoyl Peroxide Gel (Tactuo™)

• This new fixed-dose (adapalene 0.1%-BPO 2.5%) topical agent is the first retinoid-BPO combination formulation.
• Applied once daily.
• Three double-blind randomized controlled trials^4-6 including a total of 3855 acne patients compared the efficacy of adapalene-BPO with adapalene, BPO, and gel vehicle. All three studies showed statistically significant superior efficacy of the adapalene-BPO combination over the three comparison treatments in total or near total clearing of acne and reduction in total number of inflammatory and noninflammatory lesions.
• An analysis of these three studies demonstrates a synergistic effect beyond that attributable to each agent alone:⁷
  • 1.2% of patients discontinued due to adverse events
  • 21.6% of patients experienced adverse events including dryness, erythema, scaling, and stinging/burning
  • Adverse events had a mean rating of “below mild” and peaked at week 1, then improved

Clindamycin-Tretinoin Gel (Biacna®)

• A new clindamycin-tretinoin fixed-dose combination gel is available.
• Applied once daily.
• Two randomized, double-blind, controlled trials⁸ of 2219 subjects compared the combination clindamycin-tretinoin hydrogel with each agent alone and gel vehicle for the treatment of acne vulgaris. The studies both showed statistically significant superior efficacy of the clindamycintretinoin combination over either agent alone or vehicle in reducing the number of inflammatory and noninflammatory lesions and inducing near or total clearing of the skin, with good tolerance.
• This formulation should be not be used for maintenance therapy and use in conjunction with a BPO product is recommended to limit antibiotic resistance.¹

Systemic Treatment Considerations

• Patients with severe inflammatory acne will likely require
  systemic therapy.
• Patients with moderate acne may also need systemic therapy,
  after adherence to topical therapies is assessed.
• Investigation for endocrine causes of acne may be indicated
  in cases with atypical clinical presentation, cases that
  are particularly severe and treatment resistant, or those
  associated with systemic signs and symptoms of endocrine
  disturbance. In females patients, exclude polycystic ovary
  syndrome, adrenal or ovarian tumors, and congenital
  adrenal hyperplasia. In males, exclude congenital adrenal
  hyperplasia.
• Systemic therapies include:³
  • Oral antibiotic + topical retinoid ± BPO
  • Oral isotretinoin
  • Oral contraceptive/anti-androgen for female patients

Limiting Antibiotic Resistance

• Oral antibiotics can cause resistance in bacterial flora throughout the body, while topical antibiotics can cause resistance of skin flora at the treated site.
• Recommendations to limit antibiotic resistance:¹
  • Reserve oral antibiotics for moderate to severe acne
  • Topical and systemic antibiotics should always be combined with BPO and a topical retinoid
  • Limit antibiotic duration: assess response and continuing need at 6-12 weeks
  • If multiple courses of antibiotics are required avoid unnecessary antibiotic switches (use the same one each time if effective)
  • Use BPO along with antibiotics (BPO is an efficient bactericidal agent and will minimize development of bacterial resistance at sites of topical antibiotic therapy)
  • Avoid oral or topical antibiotic monotherapy for acute or maintenance therapy
  • Avoid concurrent oral and topical antibiotic therapy without the addition of BPO

Maintenance Therapy

• A topical retinoid ± BPO is first-line maintenance therapy1 because it effectively controls the formation of microcomedones, is well-tolerated, and does not contribute to antibiotic resistance.
• For patients with mild to moderately severe acne, regardless of the type of therapy used to treat the acute episode of acne, a retinoid-based topical maintenance regimen should be initiated once lesions have resolved. For patients with severe acne, a different approach may be required.¹
• Because of the complex interplay of acne pathogenic factors, maintenance therapy may need to be continued for months to years.
• Patients should be advised that acne might follow a chronic pattern of remissions and outbreaks, which are best managed with maintenance therapy to control the formation of microcomedones before acne lesions become visible.
• Regular follow-up visits at least every 6 months during maintenance therapy will allow for assessment of treatment response, side-effects, and adherence.

Conclusion

Acne is a very common skin disorder predominantly managed in the family practice setting. In conjunction with patient education and a strong therapeutic alliance, retinoid-based topical agents for acute and maintenance therapy, including strategies to limit antibiotic resistance, are effective for mild to moderately severe acne, with few adverse effects and improved quality of life for affected patients.

References

1. Thiboutot D, et al. J Am Acad Dermatol 60(5 Suppl):S1-50 (2009 May).
2. Bowe W, et al. J Am Acad Dermatol 63(1):124-41 (2010 Jul).
3. Gollnick H, et al. J Am Acad Dermatol 49(1 Suppl):S1-38 (2003 Jul).
4. Thiboutot DM, et al. J Am Acad Dermatol 57(5):791-9 (2007 Nov).
5. Gold LS, et al. Cutis 84(2):110-6 (2009 Aug).
6. Gollnick HPM, et al. Br J Dermatol 161(5):1180-9 (2009 Nov).
7. Tan J, et al. J Dermatolog Treat [Epub 2010 Jul 28].
8. Leyden JJ, et al. J Am Acad Dermatol 54(1):73-81 (2006 Jan).

Department of Dermatology and Skin Science, University of British Columbia,
Vancouver, Canada

ABSTRACT

Common diaper dermatitis is an irritant contact diaper dermatitis (IDD) created by the combined influence of moisture, warmth, urine, feces, friction, and secondary infection. It is difficult to completely eradicate these predisposing factors in a diapered child. Thus, IDD presents an ongoing therapeutic challenge for parents, family physicians, pediatricians, and dermatologists. This article will focus on practical management strategies for IDD.

Key Words:
diaper dermatitis, IDD

IDD is a common inflammatory eruption of the skin in the diaper area created by the presence of moisture, warmth, urine, feces, and friction, and is seen in 25% of children wearing diapers.¹

Pathogenesis

Four key factors contribute to the development of IDD:²

Wetness

• Wet diapers result in excessive hydration and maceration of the stratum corneum3 leading to impaired barrier function, enhanced epidermal penetration by irritants and microbes, and susceptibility to frictional trauma.⁴

Friction

• IDD is most commonly distributed in areas with the greatest skin-to-diaper contact.⁵
• Mechanical trauma disrupts the macerated stratum corneum, exacerbating barrier dysfunction.

Urine and feces

• Candida albicans (C. albicans) and, less commonly, Staphylococcus aureus (S. aureus) infections are associated with IDD.⁸
• The warm, humid, and high pH environment in the diaper provides the ideal milieu for microbial proliferation.
• Innate antimicrobial microflora cannot survive in a high pH environment.⁹
• There is a positive correlation between the clinical severity of IDD and the presence and level of C. albicans in the diaper, mouth, and anus of infants.⁸

Microorganisms

• The interaction of urine and feces is key to the pathogenesis of IDD. Bacterial ureases in the stool degrade the urea that is found in urine, releasing ammonia and increasing local pH.⁶
• Fecal lipases and proteases are activated by the increased pH. They cause skin irritation and disruption of the epidermal barrier.⁷
• Ammonia does not irritate intact skin; it is thought to mediate irritation by contributing to the high local pH.⁶

Clinical Features

IDD initially presents with localized asymptomatic erythema, and can progress to widespread painful, confluent erythema with maceration, erosions, and frank ulceration.10 IDD commonly spares the skin folds, and affects the convex skin surfaces in close contact with the diaper including the buttocks, genitalia, lower abdomen, and upper thighs. IDD complicated by Candida presents with beefy red intertriginous plaques and satellite papules and pustules in the diaper area. IDD complicated by S. aureus appears impetiginized, with erosions, honey-colored crust, and lymphadenopathy.

Granuloma gluteale infantum and Jacquet erosive diaper dermatitis are distinctive, severe variants of IDD. Granuloma gluteale infantum presents in the setting of IDD with violaceous papules and nodules on the buttocks and in the groin. The pathogenesis of granuloma gluteale infantum is not clear. Potential risk factors include treatment with topical steroids,¹¹ candida infection, and occlusive plastic diaper covers.¹² Granuloma gluteale infantum follows a self-limited course, resolving in weeks to months, often with residual scarring.^5,11 The presence of punched-out erosions or ulcerations with heaped-up borders characterizes Jacquet erosive diaper dermatitis. This uncommon and severe presentation of IDD typically occurs in the context of frequent liquid stools, poor hygiene, infrequent diaper changes, or occlusive plastic diapers.¹²

It is imperative to consider other conditions that may occur in the diaper area. Several excellent references are available that outline the differential diagnosis of IDD.^5,13 Please see Table 1 for a review of the clinical features of relevant diaper dermatoses.

Risk Factors

Fecal incontinence and diarrhea are risk factors for severe IDD because of prolonged and frequent skin contact with stool. Examples of at-risk children include those with Hirschsprung’s disease, fecal impaction and overflow, and anogenital malformations.14 Fecal proteases and lipases are also upregulated when gastrointestinal transit time is low.⁹ Increased bile acids in stool, seen in short gut syndrome and conjugated hyperbilirubinemia, also increase protease activity.¹² Children with atopic dermatitis are prone to IDD because of their sensitivity to irritants and a greater susceptibility to secondary infection.

Treatment

Diapers

The continuous use of diapers is at the root of IDD. Maximizing “diaper-free” time is a widely recommended preventative strategy, but is not very practical. Frequent diaper changes are essential for maintaining dryness and keeping urine and feces separated. Diapers should be changed as soon as they are wet or soiled, at least every 3–4 hours and more frequently in the neonate due to increased skin fragility.¹⁵ Parents should forego tight-fitting diapers and consider a diaper slightly larger than the infant to minimize the contact between skin and urine or feces.⁵ Common IDD should resolve when children become toilet trained.

The advent of disposable diapers and the ongoing development of new diaper technology has radically changed the face of IDD. Early cellulose-core containing disposable diapers were dramatically improved by the addition of cross-linked sodium polyacrylate polymers to the diaper core.^10,16,17 These polymers, also called absorbent gelling materials, bind water in a gel matrix when hydrated.^16,17 This gel effectively traps moisture away from the skin surface. It controls pH through its buffering capacity, and by separating urine from feces.¹⁷ These diapers are referred to as superabsorbent diapers.¹⁶ In a study of 1,614 infants, superabsorbent diapers were associated with reduced skin wetness, superior
pH control, and less diaper dermatitis compared with cellulose-core disposable and cloth diapers.¹⁷ Originally, these diapers were developed with an impenetrable backsheet (outer cover) to prevent leaks, but this led to increased humidity and skin maceration. A “breathable” diaper was subsequently developed with a backsheet that is permeable to air and vapor but still impenetrable to leaks.16 This backsheet is readily identified by its cloth-like, rather than plastic, texture. The “breathable” superabsorbent diaper has been shown to reduce the prevalence of severe IDD by up to 50%.¹⁰ Nearly all commercially available disposable diapers in North America now use polyacrylate gel-core technology, and many use the breathable backsheet (e.g., Pampers^®, Procter & Gamble; Huggies^®, Kimberly-Clark). A novel diaper has recently been developed that transfers a petrolatum and zinc oxide-based formula to the child’s skin.¹⁸ In a double-blinded, randomized trial, infants using this diaper had consistently less skin erythema and diaper rash compared with those using a superabsorbent diaper alone over a 4-week period of use.¹ Cloth diapers are not recommended for patients with IDD. They increase skin wetness, promote mixing of urine and feces, and are associated with Jacquet erosive diaper dermatitis.¹²

Barrier

Application of a suitable barrier preparation is the cornerstone of prevention and treatment of IDD. There is a notable absence of controlled trials to support and guide the use of barrier preparations for IDD. Anecdotal evidence is abundant and suggests a barrier preparation should be applied to the diaper area after every diaper change and bath. A suitable barrier preparation should minimize transepidermal water loss (TEWL) and decrease permeability to irritants.⁹ The barrier corrects these deficits by forming a lipid barrier over the skin surface, or by penetrating the stratum corneum and assuming the role of endogenous intercellular lipids.^5,19 The barrier also minimizes cutaneous friction. The barrier must be lipid-rich, long-lasting and adherent to the macerated and eroded diapered skin.

Pastes are the most hardy and desirable barriers, followed by ointments. Ointments are superior to creams and lotions, which are poorly adherent, minimally occlusive, and contain preservatives. Diaper pastes are tenacious semisolid compounds containing a high
proportion (usually >10%)9 of a fine powder such as zinc oxide, titanium dioxide, and starch or talc.²⁰ Pastes should be applied thickly, like “icing on a cake”, and can be covered by petroleum jelly to avoid sticking to the diaper.¹⁴ Products containing fragrance, preservatives, and other ingredients with irritant or allergic potential should be avoided. Products containing boric acid, camphor, phenol, and salicylates should be avoided due to potential systemic toxicity.²¹ The local ostomy nurse may also be a valuable resource in identifying suitable barrier preparations in severe IDD.

Cleansing

Children predisposed to IDD should be bathed daily in a lukewarm bath using an irritant-free and fragrance free soap or cleanser followed by liberal application of a barrier preparation to the diaper area. The diaper area should be cleaned gently and dried by patting with a towel to avoid any undue friction. Aggressive wiping at diaper changes should be avoided. Residual adherent barrier paste does not need to be wiped off along with the urine and stool at each diaper change. Mineral oil can help facilitate paste removal, if required.^5,14

It is a commonly held belief that baby wipes contribute to IDD; however an investigator-blinded, parallelcomparison study of 102 infants found no difference between skin cleaned with an alcohol-free, nonwoven disposable wipe, and skin cleaned with water and a cleanser.²² Moreover, skin cleaned with wipes had statistically better rash scores in the intertriginous areas, suggesting that wipes may help parents access hardto- reach areas. These wipes were found to be safe and well tolerated in infants with atopic dermatitis. Baby wipes can cause an allergic contact hand dermatitis in caregivers, in a “grip-like” distribution.²³ It is prudent to choose wipes without fragrance and preservatives to avoid allergic sensitization.

Infection

Candida infection is often associated with moderatesevere cases of IDD. C. albicans is present in the mouth, inguinal and perianal skin more frequently in patients with IDD.⁸ The azoles, nystatin, and ciclopirox are all appropriate topical anticandidal agents,^5,24 but few well-designed comparative trials are available to guide clinical practice. Twice-daily
application is recommended until resolution. In a National Ambulatory Medical Care Survey (NAMCS), more than 200,000 visits for diaper dermatitis in the US were reviewed; nystatin and clotrimazole were the most commonly prescribed topical antifungals (27% and 16% respectively).¹ A prospective, randomized study compared topical nystatin with mupirocin in the treatment of IDD complicated by C. albicans infection. Treatment with both agents resulted in mycological cure; however, resolution of IDD was observed in all patients treated with mupirocin compared with only 30% treated with nystatin.²⁵ Application of miconazole nitrate 0.25% in a zinc oxide and petrolatum base has demonstrated efficacy and safety in vehicle-controlled, randomized, double-blinded trials.^26,27 In an open trial, ciclopirox 0.77% topical suspension demonstrated significant improvement in rash severity and superior mycological cure by 7 days in patients with IDD and C. albicans infection.²⁸ There is little evidence to support the addition of an oral antifungal to topical therapy in IDD.²⁹ Patients with concomitant oral thrush, however, may benefit from a course of systemic antifungal therapy.⁵

Corticosteroids

A short course of a mild topical corticosteroid is frequently necessary in moderate-to-severe IDD. Hydrocortisone 1% ointment can be applied to affected areas twice daily for a limited duration. Mid-to-high potency corticosteroids should never be used in the diaper area. The NAMCS documented a surprisingly high rate of moderate-to-high potency halogenated topical corticosteroid use in IDD. Triamcinolone acetonide or betamethasone dipropionate use, either alone or in combination with antifungals, was documented in a staggering 24.3% of visits for diaper dermatitis.1 Atrophy, systemic absorption, candidiasis, and granuloma gluteale infantum are all associated with mid-to-high potency corticosteroid use in the diaper area. The topical calcineurin inhibitors, tacrolimus and pimecrolimus, have not been studied for the treatment of IDD. These agents have been studied for efficacy and safety as a steroid-sparing treatment for atopic dermatitis in infants < 2 years old.³⁰ Although they are not approved for use in this age group, they may be a useful off-label alternative for IDD in the appropriate clinical setting.

Other Agents

A number of other agents have been reported to be efficacious in the treatment of IDD. A recent pilot study found clinical and mycological benefits using a 1:1:1 mixture of honey: olive oil: beeswax to treat IDD.³¹ Eosin, an orange-red dye derived from coal tar, is a common agent used for IDD in Europe. It was found to have a greater rate of clearance of IDD within 5 days compared with zinc oxide and a moderate-potency topical corticosteroid ointment.³² In a randomized, vehicle-controlled study, topical vitamin A cream did not improve the outcome of IDD.³³

Conclusion

IDD is a common dermatosis afflicting diapered children. It is caused by wetness, friction, urine, stool, and microorganisms. A proactive approach targeting predisposing factors is the best defence against IDD.

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